Skip to main content
SpringerLink
Log in

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV self-emulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

REFERENCES

  1. Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discovery Today. 2010;15(21–22):958–65.

    Article  PubMed  CAS  Google Scholar 

  2. Kuentz M. Oral self-emulsifying drug delivery systems, from biopharmaceutical to technical formulation aspects. J Drug Deliv Sci Technol. 2011;21(1):17–26.

    CAS  Google Scholar 

  3. Kaukonen AM, Boyd BJ, Charman WN, Porter CJ. Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res. 2004;21(2):254–60.

    Article  PubMed  CAS  Google Scholar 

  4. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12(11):1561–72.

    Article  PubMed  CAS  Google Scholar 

  5. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm Sci. 2000;11 Suppl 2:S93–8.

    Article  PubMed  CAS  Google Scholar 

  6. Charman WN. Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts. J Pharm Sci. 2000;89(8):967–78.

    Article  PubMed  CAS  Google Scholar 

  7. Fatouros DG, Bergenstahl B, Mullertz A. Morphological observations on a lipid-based drug delivery system during in vitro digestion. Eur J Pharm Sci. 2007;31(2):85–94.

    Article  PubMed  CAS  Google Scholar 

  8. Lim WH, Lawrence MJ. Influence of surfactant and lipid chain length on the solubilisation of phosphatidylcholine vesicles by micelles comprised of polyoxyethylene sorbitan monoesters. Colloid Surf A. 2004;250(1–3):449–57.

    Article  CAS  Google Scholar 

  9. Lim WH, Lawrence MJ. Aggregation behaviour of mixtures of phosphatidylcholine and polyoxyethylene sorbitan monoesters in aqueous solution. Phys Chem Chem Phys. 2004;6(7):1380–7.

    Article  CAS  Google Scholar 

  10. Ljusberg-Wahren H, Seier Nielsen F, Brogard M, Troedsson E, Mullertz A. Enzymatic characterization of lipid-based drug delivery systems. Int J Pharm. 2005;298(2):328–32.

    Article  PubMed  CAS  Google Scholar 

  11. Li Y, Hu M, McClements DJ. Factors affecting lipase digestibility of emulsified lipids using an in vitro digestion model: proposal for a standardised pH-stat method. Food Chem. 2011;126(2):498–505.

    Article  CAS  Google Scholar 

  12. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    Article  PubMed  CAS  Google Scholar 

  13. Mohsin K, Long MA, Pouton CW. Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J Pharm Sci. 2009;98(10):3582–95.

    Article  PubMed  CAS  Google Scholar 

  14. Constantinides PP, Scalart J-P, Lancaster C, Marcello J, Marks G, Ellens H, et al. Formulation and intestinal absorption enhancement evaluation of water-in-oil microemulsions incorporating medium-chain glycerides. Pharmaceut Res. 1994;11(10):1385–90.

    Article  CAS  Google Scholar 

  15. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm. 2000;50(1):179–88.

    Article  PubMed  CAS  Google Scholar 

  16. Brogard M, Troedsson E, Thuresson K, Ljusberg-Wahren H. A new standardized lipolysis approach for characterization of emulsions and dispersions. J Colloid Interface Sci. 2007;308(2):500–7.

    Article  PubMed  CAS  Google Scholar 

  17. Cuine JF, McEvoy CL, Charman WN, Pouton CW, Edwards GA, Benameur H, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs. J Pharm Sci. 2008;97(2):993–1010.

    Article  Google Scholar 

  18. Larsen AT, Sassene P, Mullertz A. In vitro lipolysis models as a tool for the characterization of oral lipid and surfactant based drug delivery systems. Int J Pharm. 2011;417(1–2):245–55.

    Article  PubMed  CAS  Google Scholar 

  19. Alvarez FJ, Stella VJ. The role of calcium ions and bile salts on the pancreatic lipase-catalyzed hydrolysis of triglyceride emulsions stabilized with lecithin. Pharm Res. 1989;6(6):449–57.

    Article  PubMed  CAS  Google Scholar 

  20. MacGregor KJ, Embleton JK, Lacy JE, Perry EA, Solomon LJ, Seager H, et al. Influence of lipolysis on drug absorption from the gastro-intestinal tract. Adv Drug Deliver Rev. 1997;25(1):33–46.

    Article  CAS  Google Scholar 

  21. Sek L, Porter CJ, Charman WN. Characterisation and quantification of medium chain and long chain triglycerides and their in vitro digestion products, by HPTLC coupled with in situ densitometric analysis. J Pharm Biomed Anal. 2001;25(3–4):651–61.

    Article  PubMed  CAS  Google Scholar 

  22. Sek L, Porter CJ, Kaukonen AM, Charman WN. Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products. J Pharm Pharmacol. 2002;54(1):29–41.

    Article  PubMed  CAS  Google Scholar 

  23. Jurado E, Fernandez-Serrano M, Nunez-Olea J, Luzon G, Lechuga M. Simplified spectrophotometric method using methylene blue for determining anionic surfactants: applications to the study of primary biodegradation in aerobic screening tests. Chemosphere. 2006;65(2):278–85.

    Article  PubMed  CAS  Google Scholar 

  24. Cuine JF, Charman WN, Pouton CW, Edwards GA, Porter CJ. Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs. Pharm Res. 2007;24(4):748–57.

    Article  PubMed  CAS  Google Scholar 

  25. Wiedmann TS, Kamel L. Examination of the solubilization of drugs by bile salt micelles. J Pharm Sci. 2002;91(8):1743–64.

    Article  PubMed  CAS  Google Scholar 

  26. Dahan A, Hoffman A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res. 2006;23(9):2165–74.

    Article  PubMed  CAS  Google Scholar 

  27. Christensen JO, Schultz K, Mollgaard B, Kristensen HG, Mullertz A. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols. Eur J Pharm Sci. 2004;23(3):287–96.

    Article  PubMed  CAS  Google Scholar 

  28. Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliver Rev. 1997;25(1):47–58.

    Article  CAS  Google Scholar 

  29. Najib J. Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation. Clin Ther. 2002;24(12):2022–50.

    Article  PubMed  CAS  Google Scholar 

  30. Humberstone AJ, Charman WN. Lipid based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev. 1997;25(1):103–28.

    Article  CAS  Google Scholar 

  31. Narayanan VS, Storch J. Fatty acid transfer in taurodeoxycholate mixed micelles. Biochemistry. 1996;35(23):7466–73.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS

KM thankfully acknowledges the financial support provided by Abbott Laboratories during this project. The author is also grateful to Prof Colin Pouton and Dr Michelle Long for their necessary assistance during this study.

Author information

Authors and Affiliations

  1. Kayyali Chair for Pharmaceutical Industries, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box-2457, Riyadh, 11451, Kingdom of Saudi Arabia

    Kazi Mohsin

Authors
  1. Kazi Mohsin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazi Mohsin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mohsin, K. Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drug Fenofibrate: Effects of Digestion. AAPS PharmSciTech 13, 637–646 (2012). https://doi.org/10.1208/s12249-012-9787-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-012-9787-2

KEY WORDS

Search

Navigation